Adequate calcium intake is critical for normal skeletal growth and is necessary for the prevention of osteoporosis. Often, calcium supplementation of the diet is needed to achieve this intake. Calcium is an important human dietary component. Calcium is required for adequate bone formation and maintenance, as well as for diverse metabolic functions. These diverse metabolic functions of calcium are incompletely understood but likely involve, at least in part, the alteration and functional control of proteins such as enzymes.
An assurance of adequate dietary calcium intake is thus important for normal development, metabolism and maintenance. Dietary calcium intake alone however is insufficient to assure that adequate calcium levels are available for required body functions. Dietary calcium must be absorbed from the digestive tract before it may be utilized. The intestinal absorption of calcium is enhanced by vitamin D and may also be affected by the particular chemical form of ingested calcium. Furthermore, the urinary excretion of absorbed calcium must be considered, particularly for individuals who may be subject to the formation of calcium-containing kidney stones.
Among the pathologies of particular relevance to calcium dietary requirements is osteoporosis. Osteoporosis, a condition characterized by decreases in bone mass, renders bones more fragile and susceptible to fracture. The increasingly older population of this country, since osteoporosis is usually an age-related phenomenon, further accentuates the significance of this condition. Post-menopausal women are generally agreed to be most susceptible to osteoporosis. As demonstrated by Heaney et al. (J. Lab. Clin. Med. (1978) Vol. 92 No. 6 pp. 953 to 963), postmenopausal women, unless treated with estrogens, required an increased calcium intake to maintain a zero calcium balance. This increased required intake was ascribed as due to a decrease in the production of an active vitamin D compound and calcium absorption, both perhaps related to the absence of estrogens. Recker et al. (Annals Int. Med. (1977) Vol. 87 No. 6 pp. 649 to 655) demonstrated that further bone losses in osteoporosis prone postmenopausal women may be prevented by estrogen treatment or, to a lesser extent, by dietary calcium carbonate supplementation.
In an additional study concerning osteoporosis of postmenopausal women, Nordin et al. (Brit. Med. J. (1980) Vol. 280 pp. 451 to 454) found three treatments that succeeded in lessening or abolishing further bone deterioration. These three treatments were: dietary calcium supplementation; estrogenic hormone treatment; and, treatment with estrogenic hormone plus 1-alpha hydroxy vitamin D.sub.3.
Treatment of individuals with estrogenic hormones may have adverse effects, such as the stimulation of estrogen dependent tumors. Treatment of individuals with vitamin D derivatives may be inadvisable because of potentially toxic effects when excess vitamin D is administered. An effective dietary calcium supplementation appears to be an advisable treatment for osteoporosis.
The interrelation of calcium and hypertension has recently been the focus of much research. McCarron et al (Science (1982) Vol. 217 pp. 267 to 269) found that subjects with essential hypertension had a lower daily calcium intake (668.+-.89 mg) then that of normotensive subjects. McCarron (N. Eng. J. Med. (1982) Vol. 307 pp. 226 to 228) indicated that while normotensive subjects and hypertensive subjects had similar serum levels of total calcium, the hypertensive subjects had lower serum levels of ionized calcium. Ackley et al. (Am. J. Clin. Nutr. (1983) Vol. 38 pp. 457 to 461) reported finding that hypertensive men consumed significantly less milk, a major source of dietary calcium, than did normotensive men.
Belizan et al. (J. Am. Med. Ass'n. (1983) Vol. 249 No. 9 pp. 1161 to 1165) indicated that young adults showed reduction in blood pressure when their diets were supplemented with 1 gm/day elemental calcium (calcium carbonate and calcium lactate-gluconate). A similar observation was made with pregnant women (Belizan et al. Am. J. Obstet. Gynecol (1983) Vol. 146 No. 2 pp. 175 to 180). Currently, a possibility exists that adequate calcium intake may be an important factor in control of blood pressure.
The interrelationship of calcium and chronic diarrheal syndrome has also been studied. This syndrome, where bone loss may occur, may result from surgical resection or inflammation of the digestive tract. Bone disease may occur because patients with this condition absorb calcium poorly from intestines. Thus, a calcium supplement might help prevent bone loss in these patients.
In chronic kidney disease, hyperphosphatencia (high blood phosphorus) may develop from the inability of the kidneys to eliminate phosphate. Calcium supplementation may also be useful here, by binding phosphate and preventing its absorption in the intestinal tract.
Supplementation of the diet with calcium appears to be an important step for the prevention and treatment of calcium related pathologies including osteoporosis, possibly hypertension, and bone loss in chronic diarrheal syndrome, and phosphate accumulation in chronic renal failure. Ideally, to be most effective, a calcium supplement should satisfy the following criteria: (1) it should dissolve readily in the gastric juice so that it can eventually be absorbed in the more distal part of the bowel; (2) it should not precipitate out of duodenal juice when the juice is alkalinized by pancreatic bicarbonate secretions; (3) it should not be "complexed" extensively by negatively charged substances in the upper part of the small bowel, a process that could reduce the amount of absorbable ionic calcium; (4) it should not have as one of its side effects the formation of kidney stones; and (5) it should be in a tablet form which can be easily swallowed without adverse gastrointestinal symptoms.
Some calcium supplements, such as tricalcium dicitrate, satisfy some of the above criteria. Tricalcium dicitrate was found to be more soluble in gastric juice than calcium carbonate, the most widely used calcium salt (Pak, CRN Quarterly, 12:8-10, 1988). Moreover, tricalcium dicitrate did not precipitate out of simulated duodenal juice (Pak, et al., J. Clin. Endoc. Metab., 65:801-805, 1987). The development of ultradense tableting technology allowed tricalcium dicitrate to be manufactured as a small, easily swallowed tablet. Tricalcium dicitrate also increased urinary citrate, which decreases the likelihood of kidney stone formation (Harvey, Zobitz and Pak, J. Clin. Endoc. Metab., 61:1223-1225, 1985).
Because of their high aqueous solubility it was believed that calcium lactate or calcium gluconate would present advantages over tricalcium dicitrate supplementation. However, the calcium content for these salts is low, being 13% and 9%, respectively. Thus, to deliver a therapeutically effective amount of calcium (0.2 grams to 2.0 grams/day), in a tablet form would require an unacceptably large tablet. Moreover, these salts are not as effective as tricalcium dicitrate in raising urinary citrate. Accordingly, these salts do not as effectively decrease the likelihood of calcium-containing kidney stone formation that could occur from calcium supplementation.
However, even a calcium supplement as effective as tricalcium dicitrate does not satisfy all of the criteria for an ideal supplement. Tricalcium dicitrate preparations, for example, may not dissolve completely, under certain conditions, in states of basal or low gastric acid secretion. Furthermore, large amounts of solubilized calcium become complexed to citrate in the proximal bowel where a substantial portion of calcium is absorbed. It is believed that ionic calcium is better absorbed (bioavailable) than complexed calcium. Thus, formation of a soluble calcium-citrate complex could lower the amount of calcium absorbed by reducing the total ionic calcium pool.
Dietary calcium supplementation is generally considered an effective method for preventing or treating a calcium deficiency or pathology related to such deficiency. However, typical available dietary calcium supplements are often plagued by the problems of poor absorption, low calcium content, poor solubility in gastric juice, and insufficient bioavailability of solubilized calcium. Thus, a new calcium supplement which effectively overcomes these problems is needed. The dietary calcium supplement of the present invention provides an answer to such needs.